Psychosis occurs in 40-60% of subjects with Alzheimer disease (Alzheimer disease + Psychosis, AD+P). AD+P is associated with greater cognitive impairment and more rapid cognitive and functional deterioration than in AD without psychosis (AD-P). We and others have shown that AD+P aggregates in families, indicating it may arise from a distinct underlying neurobiology. Prior studies have indicated that the strongest correlate of cognitive impairment in individuals with AD is loss of synapses across neocortical regions, with excitatory synapses onto dendritic spines particularly affected. Recently, evidence from cell culture, transgenic mice, and post-mortem human studies have provided converging evidence that soluble amyloid beta (A() initiates a pathophysiologic cascade leading to synapse disruption in AD. Soluble A( can cause spine loss by shifting the balance of post-synaptic signaling within spines from pathways supporting long-term potentiation (LTP) to those supporting long-term depression (LTD) and via increasing aggregation of microtubule-associated protein tau (MAPT). These findings suggest a model in which the more rapidly deteriorating cognitive course of individuals with AD+P reflects a greater degree of cortical synaptic disruption than found in AD subjects without psychosis (AD-P) due to the effects of soluble A( and/or downstream effectors of A(-induced spine dysfunction and loss. In support of this model, we have previously reported biochemical evidence consistent with increased synaptic disruption across multiple neocortical regions in subjects with AD+P, and have preliminary data indicating that soluble A(1-42 is increased in AD+P versus AD-P subjects. We now propose to further examine this model in postmortem tissue from an existing cohort of subjects with AD+P and AD-P. We will test the following hypothesis: 1) Soluble A(1-42 concentrations are increased in AD+P relative to AD-P subjects, while soluble A(1-40 is not; 2) Number and density of dendritic spines are reduced in subjects with AD+P in comparison to subjects with AD-P; 3) Effectors of LTP (Kalirin7 and PAK1) are reduced, and an effector of LTD (Calcineurin) is elevated, in AD+P compared to AD-P subjects; and 4) increased MAPT aggregation is present in AD+P relative to AD-P subjects. The inter- relationships of these factors will be examined in exploratory analyses examining their independent and mediating effects. The planned investigations are novel and benefit from access to a high quality brain tissue resource in which all subjects have undergone state-of-the- art standardized clinical and neuropathologic assessments, including structured antemortem behavioral assessments of psychosis. Successful completion of the planned analyses will inform whether: 1) there is excess loss of dendritic spines in neocortex of AD+P subjects; 2) the degree of spine loss is correlated with concentrations of soluble A(, or alternatively, 3) correlated with concentrations of aggregated MAPT and/or mediators of structural LTP and LTD. This knowledge base will serve to generate mechanistic hypotheses regarding the causal pathways resulting in excess synaptic disruption in AD+P that can be tested in future studies using additional animal and/or in vitro experimental models. PUBLIC HEALTH RELEVANCE: Facilities & Other Resources Highland Drive Campus B4R207W - 240Sq. ft., B4R229SW - 910Sq. ft.; Partial offsite waiver appended for Dr. Sweet's laboratories (W1603, W1604, W1606) in the floor of the Biomedical Science Tower (BST), University of Pittsburgh. Laboratory Approximately 2,800 sq. ft. is available for this project in the Biomedical Science Tower (BST). The laboratories consist of separate facilities for tissue fixation and preparation, immunocytochemistry and other histological procedures, western blotting, and computer-assisted microscopy and image analysis. Computer The laboratories are equipped with the following computers: Dell PowerEdge 4400 with dual 733 MHz Xeon processors Novell Server, used for maintaining the database of brain specimens and running the web server. It is also used as the file server. Four Dell Precision Workstations which range from an 800 MHz Pentium III to a 2.2 GHz Pentium IV; one Pentium II computer, six Pentium III computers in the 400 MHz to 866 MHz range, two Pentium III computers in the 1 to 2 GHz range, twenty Pentium IV computers in the 2.0 to 3.1 GHz range, and three Pentium IV computers in 2.0 to 2.4 GHz range, used for general use and imaging. AGFA Arcus Scanner and a Microtek ArtixScan 2500 Scanner. One Hewlett Packard color laser printer; ten Hewlett Packard black and white laser printers; Fuji Pictrography 3000 printer. Office Dr. Sweet has shared office space at the Highland Drive Campus, where an office for the data manager is also located. Drs. Sweet, Ikonomovic and Fish have offices located adjacent to their laboratories in the Biomedical Science Tower (BST). Other A shared histology laboratory, darkroom, coldroom, low temperature freezers, small animal perfusion room, equipment room and glasswashing facility are also located on the 16th floor of BST. Machine and electronic shops, housed in Crawford Hall, are available for the Translational Neuroscience Program faculty's use.